Rossello lost the New Progressive Party Gubernatorial Primary in 2008. In 2003 Rosselló made a comeback, winning the NPP's 2004 gubernatorial nomination in primaries against then-NPP President Carlos Pesquera. He then lost the 2004 gubernatorial race to Aníbal Acevedo Vilá by an unprecedented and a vigorously disputed razor-thin margin. Soon after an elected NPP Senator from Arecibo resigned his seat and Rosselló filled the vacancy. From 2005 to 2006 Rosselló unsuccessfully sought to remove Senate President Kenneth McClintock from his seat and replace him. In 2008 Rosselló lost the NPP’s 2008 gubernatorial nomination to then-Resident Commissioner and current Governor Luis Fortuño. Thereafter he completed his term as Senator and retired from active politics.

Roselló was born in San Juan, on April 5, 1944. After completing his elementary and secondary education at Academia Santa Teresita and Academia del Perpetuo Socorro, both located in San Juan, Rosselló moved to the mainland United States to attend college. He earned his Bachelor of Science degree, Magna Cum Laude at the University of Notre Dame in 1966, as well as several academic and athletic distinctions. After graduation, he continued his studies in medicine at Yale University, which he completed in 1970, also graduating Magna Cum Laude. Later he specialized in general and pediatric surgery at Harvard University. Following his residency at Harvard, he practiced medicine in Puerto Rico while also attending the University of Puerto Rico, Medical Sciences Campus where he earned a Master's in Public Health (MPH) degree in 1981 (also graduating Magna Cum Laude). He later pursued a graduate degree in Education from the InterAmerican University of Puerto Rico. During his college years, Rosselló became an avid tennis player that led him to be named the captain of Notre Dame's Men's tennis team, a P.R. 5-time-Mens-Champion, and also to play for Puerto Rico's team in regional championships, including the Central American and Caribbean Games. He was inducted into the Puerto Rico Tennis Hall of Fame in 2004.

Rosselló started his professional career alternating as an instructor at Harvard Medical School and as an assistant professor at the University of Puerto Rico, Medical Sciences Campus, where he would later become an associate professor.

He became Chief of Pediatric Surgery and later Chief Surgeon at the University of Puerto Rico Children's Hospital. In 1985, Rosselló was named Health Services Director for the city of San Juan by then Mayor Baltasar Corrada del Río.

As governor, Rosselló launched an anti-crime campaign known as "Mano Dura Contra el Crimen" (literally, "Strong hand against crime") in which the Puerto Rico National Guard was used to assist state police in detering the ever-increasing crime wave that had begun in the late 1980s. This crime-fighting initiative managed to reduce violent crimes in half by the time he left office in Jan. 2001. He also worked to eradicate drug traffic in Puerto Rico Publics School on his campaign "Zona Libre de Drogas" ( Free Drug Zone). His administration was also characterized for investing in large-scale infrastructure projects which included a train system, dubbed Tren Urbano, and a new convention center in San Juan, now officially named[1] the Pedro Rosselló Convention Center. His policies also included a push towards reducing the size of government and taking government out of areas in which it should not act as a direct competitor of the private sector. His administration reduced the unemployment to less than 11% in 2000 creating thousands of jobs during his 8 years of government. Some other large-scale infrastructure projects were the Coliseum of Puerto Rico, the Museum of Art of Puerto Rico, the 66 highway, the SuperAcueducto,

Under his administration, a healthcare reform bill was approved. Rosselló's Health Reform made Puerto Rico one of the few jurisdictions in the entire world to have had virtually 100% of its population covered by health insurance. Additionally, under this Reform, Puerto Rico became the only jurisdiction in the USA to have nearly 100% of its infants under the age of 2 vaccinated. He led two campaigns for Puerto Rican statehood in 1993 and 1998 in which locally enacted plebiscites were held to consult the Puerto Rican electorate on the political status with the United States. He supported the congressional Young Bill, which sought to carry out a referendum in Puerto Rico to define the political status of the island. However, the bill died in committee in the Senate of the United States. Nevertheless, Rosselló carried out a non-binding plebiscite in 1998 which gave electors four options and a fifth None of the Above column. The opposing Popular Democratic Party led a campaign to boycott the plebiscite and called the electorate to vote for the None of the Above column. The boycott was successful, as the None of the Above column – which did not represent any kind support for any status option – garnered 50.3% of the total votes.[2]

In the 1996 elections he defeated rivals Héctor Luis Acevedo (PPD), who was mayor of San Juan at the time, and Representative David Noriega (PIP), winning a second term after obtaining more than one million votes and the largest victory margin since 1964.

In 1998, a 45% stake of the state-owned Puerto Rico Telephone Company (PRTC) was sold to a consortium led by GTE (now Verizon) and Banco Popular de Puerto Rico, with another stake set aside to benefit allof the company's employees. This sale led to a general strike organized by several labor unions. A similar attempt to privatize PRTC in 1988, under then Governor Rafael Hernández Colón, led to a similar strike which doomed the sale. Rosselló was successful in his plan to sell PRTC. The Telecommunications Act of 1996 deregulated the monopolies many regional telephone and cable television companies held. From then on, PRTC's telecommunications monopoly would no longer be able to properly compete in the environment and the losses to the government would have been onerous. The sale price was 2 billion dollars, which union leaders described as "ridiculously low" (PRTC generated about a 100 million dollars of yearly profit at the time of the sale)

In April 1999, a U.S. Navy bomber misfired its missiles at a practice range and struck the main watch-post on the island of Vieques, killing David Sanes, a civilian employee of the Navy. The protests that followed on the small island gathered international attention (see Navy-Vieques protests). Governor Rosselló supported the immediate exit of the Navy, appearing before the SenateArmed Services Committee pressing the Senators, among them John Warner and James Inhofe, to immediately take action so that the Navy could withdraw its troops from the island. In 2000, Rosselló and then President Bill Clinton signed an agreement that the Navy would withdraw from Vieques by the year 2003, if voters in Vieques ratified the agreement in a referendum. The agreement included $40 million in public works in Vieques. After Clinton and Rosselló left office, the administration of the next Governor of Puerto Rico, Sila Calderón, rescinded this agreement. Despite political grandstanding from the Calderón administration calling of an earlier withdrawal, the Navy left Vieques on May 1, 2003, the very same date President Clinton and Governor Rosselló had agreed upon.

In 2003, Rosselló returned to politics and won his party's nomination for the gubernatorial candidacy in a primary election against his successor as PNP leader, Carlos Pesquera. In the 2004 Puerto Rico Elections the PNP won majorities in both houses of the Legislature, the mayorships of 42 of the island's 78 municipalities and the Resident Commissioner post in the U.S. Congress. However, the position of governor was given then to incumbent Resident Commissioner Aníbal Acevedo Vilá who won by razor-thin margin in a highly controversial PR Supreme Court decision that many still hold was politically motivated.

Prior to assuming office as Senator, Rosselló had announced his intention to remove Senate President Kenneth McClintock and be elected to replace him. An internal power struggle within the New Progressive Party between Rosselló and McClintock led to a split within the NPP Senate delegation in May 2005. After a caucus meeting, eleven of the seventeen senators elected by the New Progressive Party voted for Rosselló, with the other six boycotting the meeting. McClintock and five other senators, Orlando Parga, Luz Arce, Migdalia Padilla, Carlos Díaz, and Jorge de Castro Font, refused to follow the caucus' decision, denying the unanimous consent required by Senate Rules 2 and 6 to remove a President, thus permitting McClintock to remain as Senate President. The party directorate subsequently recommended that McClintock, Parga, and de Castro Font be expelled from the Party, and that Arce, Padilla, and Díaz be censured and prohibited to run for re-election under the party's flag or logo. However, in August 2005 the party's General Assembly only took action to expel de Castro Font, leaving the status of McClintock and the other four senators in limbo after approving in August 2006 a generic censure resolution that did not name any officeholders by name. The sanctions were nullified by San Juan Superior Court Judge Oscar Dávila Suliveres on May 8, 2007. The Supreme Court of Puerto Rico, in a 5-to-1 decision, affirmed the lower court decision. Three of the disciplined senators (De Castro, Arce, Padilla) who ran for renomination, except for Díaz Olivo, were renominated in the March 2008 primary and were re-elected in the general elections.

Rosselló was able to gain a seat in the Senate of Puerto Rico when Victor Loubriel, an elected first-time district senator representing Arecibo, decided to resign his seat two days after being sworn in. The senator's resignation gave the New Progressive Party a seat it could fill, so Rosselló announced his intentions of filling the vacancy and was selected to the post through an internal party procedure. Rosselló officially assumed duties as a Senator of Puerto Rico on February 13, 2005.

On January 16, 2007, Rosselló led the party caucus in the Senate to a reprimand of two more NPP senators, fellow Arecibo senator José Emilio González and Bayamón senator Carmelo Ríos for voting in favor of a concurrent resolution proposing a constitutional amendment that would turn Puerto Rico's bicameral legislature into a unicameral legislative system, increasing the number of reprimanded caucus members to eight of the total of sixteen elected in 2004. Both González and Rios expressed their lack of concern over the reprimand and were handily renominated in the March 2008 primary and reelected in the November 2008 general election.

On February 21, 2006, Pedro Rosselló set out to make a stand against what he calls "U.S. persistent colonialism in Puerto Rico" by organizing a "March for the End of Colonialism" (La Marcha por el Fin de la Colonia). The stated purpose of the march was to expose the colonial status of Puerto Rico, and exhort the United States Congress to pass a bill that would allow the self-determination of the people of Puerto Rico, with congressionally mandated non-territorial, non-colonial options. Rosselló is a vocal and prominent supporter of statehood for the island, wanting Puerto Rico to become the 51st state of the (United States). The march covered the complete perimeter of Puerto Rico, tracing its coastline for 16 days and 271.3 miles. The United States Congress has not acted on any requests from the march's organizers.

On June 7, 2007, Senator Rosselló officially ended his bid for the Senate Presidency, stating in an article in El Vocero newspaper that he was no longer interested in the post, held since 2005 by fellow party member Kenneth McClintock. On April 19, 2007, he published a third book, El Triunvirato del Terror, (The Triumvirate of Terror) on the power centers that he believes control Puerto Rico's economy and government.

On April 28, 2007, Rosselló revealed to various party leaders that in March, 2006, he had signed a sworn statement assuring that he would not make a fourth run for the governorship in 2008, and that he intended to abide by the result. During the April 25, 2007 U.S. House Subcommittee on Insular Affairs hearing on Puerto Rico's political status, he was seen treating McClintock very cordially, which suggests that the tension levels between them had eased somewhat, suggesting he may have wanted to help reunite the party as it prepares for the 2008 electoral campaign against incumbent Governor Aníbal Acevedo Vilá and assume a different non-elective role within the statehood movement to which he has devoted nearly two decades of his life. .

During a PNP assembly on May 22, 2007 a large group of delegates unanimously acclaimed him as the party's candidate for Governor. However, given his original intention NOT to run, he officially announced that he would allow his name to be placed on the ballot, but he would not carry out a campaign for reelection. His candidacy papers were filed at the State Elections Commission on June 1, 2007. His candidacy was contested by Luis Fortuño, the current Resident Commissioner of Puerto Rico, with whom he had shared the ballot in 2004. Fortuño had also announced officially his pre-candicacy for the party's nomination for governor.

On March 9, 2008, Rosselló conceded the victory to Luis Fortuño after a large margin of votes in favor of his opponent at the primaries. [3] Rosselló admitted defeat even before the votes were completely tallied proclaiming Fortuño as the next gubernatorial candidate of the party. A day later, Rosselló sent the media a written statement regarding his future in which he confirmed he would be retiring from active politics and would not be campaigning for any candidate, committing to complete his term as senator, which he did on December 31, 2008. [4]

Groundbreaking ceremonies on November 7, 2007,[citation needed] fifteen years after his first election as Governor, marked the beginning of the construction of the Pedro Rosselló Gubernatorial Library at Turabo University's campus. To be built at a cost of $3.5 million, half of that through legislative appropriations, Puerto Rico's second gubernatorial library will house documents currently stored in 5,000 boxes.[citation needed] While the library is being built, the Rosselló collection is available to the public.[where?] Former First Lady Maga Rosselló participated in the ceremony, as well as the Ana G. Méndez University System president José Méndez.[citation needed]

Rosselló married Irma Margarita "Maga" Neváres on August 9, 1969. They have three sons: Juan Oscar (b. 1971), Luis Roberto (b. 1973), and Ricardo (b. 1979), and several grandchildren. The family’s roots in Puerto Rico go back several generations, to ancestors who migrated from Mallorca, Balearic Islands, an archipelago of Spanish islands in the Mediterranean.[5]